Allellic variants in regulatory regions of cyclooxygenase-2: association with advanced colorectal adenoma

Cyclooxygenase 2 (Cox-2) is upregulated in colorectal adenomas and carcinomas. Polymorphisms in the Cox-2 gene may influence its function and/or its expression and may modify the protective effect of nonsteroidal anti-inflammatory drugs ( NSAIDs), thereby impacting individuals' risk of developing colorectal cancer and response to prevention/intervention strategies. In a nested case control study, four polymorphisms in the Cox-2 gene ( two in the promoter, - 663 insertion/deletion, GT/(GT) and - 798 A/G; one in intron 5-5229, T/G; one in 3' untranslated region (UTR)-8494, T/C) were genotyped in 726 cases of colorectal adenomas and 729 age- and gender-matched controls in the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. There was no significant association between the Cox-2 polymorphisms and adenoma development in the overall population. However, in males, the relatively rare heterozygous genotype GT/( GT) at - 663 in the promoter and the variant homozygous genotype G/G at intron 55229 appeared to have inverse associations ( odds ratio ( OR) 0.59, confidence interval (CI): 0.34 - 1.02 and OR 0.48, CI: 0.24 - 0.99, respectively), whereas the heterozygous genotype T/C at 3'UTR-8494 had a positive association ( OR 1.31, CI: 1.01 - 1.71) with adenoma development. Furthermore, the haplotype carrying the risk-conferring 3'UTR-8494 variant was associated with a 35% increase in the odds for adenoma incidence in males ( OR 1.35, CI: 1.07 - 1.70), but the one with a risk allele at 3'UTR-8494 and a protective allele at intron 5-5229 had no effect on adenoma development ( OR 0.85, CI: 0.66 - 1.09). Gender-related differences in adenoma risk were also noted with tobacco usage and protective effects of NSAIDs. Our analysis underscores the significance of the overall allelic architecture of Cox-2 as an important determinant for risk assessment.